Polyglutamine diseases are a group of inherited neurodegenerative diseases, including Huntington's disease, caused by abnormal expansions of the polyglutamine stretch to greater the 40 repeats in the disease protein. These diseases are characterized by selective neuronal degeneration causing motor control dysfunction and, frequently, psychiatric symptoms or dementia. The polyglutamine repeat diseases are uncommon, but devastating because they are relentlessly progressive and no treatments are available. A glutamine binding peptide, QBP1, which inhibits polyglutamine protein aggregation in vitro, is a therapeutic prototype for the polyglutamine diseases. QBP1 effectively blocks polyglutamine aggregation and death in cultured cell models of disease. QBP1 also blocks polyglutamine toxicity in the eye of Drosophila expressing a polyglutamine protein with a pathologic-length repeat and normalizes lifespan. Unfortunately, delivery of therapeutic peptides to the nervous system is limited by proteolysis and poor transport across cell membranes. The goal of this one year proposal is to develop mimetics that duplicate QBPI's effect on polyglutamine repeat disease pathogenesis, by rationally designing peptide analogs which provide conformational constraint, optimize membrane permeability, protease stability, and bioavailability. The discovery process will be expedited by collaboration between Provid Pharmaceuticals (Piscataway, New Jersey), a biotechnology company devoted to developing peptidomimetic drugs, and laboratories at Duke University. During the first year of collaboration we will define the critical pharmacophore necessary for QBPI's activity in an in vitro aggregation assay, design and synthesize new analogs and test lead compounds in cellular assays. Testing a small number of mimetics for efficacy and toxicity in mouse models of polyglutamine repeat disease will be the subject of a later grant application.